Gut-immune modulation in preterm neonates: A systematic review of current evidence

Background Preterm birth remains a leading cause of neonatal morbidity and mortality globally, with significant clinical challenges related to immature immune function and disrupted gut colonization. The neonatal gut microbiota plays a crucial role in shaping immune responses during early life, particularly in preterm infants who are highly susceptible to infections and inflammatory disorders. Increasing evidence suggests that interventions targeting the gut microbiota, including the use of probiotics, prebiotics, and synbiotics, may positively influence immune development and clinical outcomes. This systematic review aimed to synthesize current evidence on gut-immune modulation strategies in preterm neonates, and evaluate their effectiveness in reducing common morbidities such as necrotizing enterocolitis and late-onset sepsis. Methods Thirty studies were included, comprising randomized controlled trials, observational studies, and meta-analyses. Probiotic supplementation, particularly with multistrain formulations, consistently reduces the incidence of necrotizing enterocolitis and late-onset sepsis. The evidence also indicated modest reductions in overall mortality, especially in settings with higher baseline risks of neonatal infection. Immunological findings suggest that probiotic interventions can promote anti-inflammatory immune profiles by enhancing regulatory cytokines while downregulating proinflammatory mediators. Despite these promising results, significant variability exists across studies regarding probiotic strains, dosages, treatment durations, and population characteristics across studies. Moreover, direct evidence linking gut modulation to long-term immune development remains limited, and safety data specific to extremely preterm infants require further investigation. Results Gut-immune modulation represents a promising approach for improving outcomes in preterm neonates, with the strongest evidence supporting probiotic supplementation for reducing gastrointestinal and infectious complications. However, further research is needed to standardize treatment protocols, explore immunological mechanisms in greater depth, and evaluate long-term safety and developmental outcomes. Addressing these gaps will be essential for guiding clinical practice and optimizing the care of preterm infants globally.